Huntington's disease (HD) is a progressive, inherited, degenerative brain disorder that produces physical, mental and emotional abnormalities in the body. This disease was earlier referred to as Huntington's Chorea, derived from the Greek word ‘choreography’, or dance. The name refers to the involuntary, jerky movements which develop in later stages of this disease. This disease is classified as a ‘rare disease’ by the Office of Rare Diseases (ORD) which is a part of the National Institute of Health (NIH), USA. This disease affects men and women indifferently and occurs in adults at variable ages.
HD is a hereditary, neurodegenerative disorder of the CNS which affects the basal ganglia of the brain. The basal ganglia are the part of the brain which controls actions of speech, movement and thought. This disease is transmitted as an autosomal dominant trait with its penetration increasing with age. The gene mutation occurs in an expansion of repeated trinucleotide sequences in the genetic make up. The genetic defect responsible for HD is a small sequence of DNA on chromosome 4 in which several base pairs are repeated many times. The normal gene has three DNA bases, composed of the sequence CAG which codes for the amino acid glutamine. In people with HD, the sequence abnormally repeats itself dozens of times, causing multiple glutamine repeats leading to a polyglutainine repeat condition. Over time, and with each successive generation, the number of CAG repeats may expand further.
HD occurs in 3 major and relatively distinct stages based on the severity of the disease: early, middle and late. In all stages of HD, weight loss is an important complication that can correspond to worsening symptoms and should be countered by adjusting the diet and maintaining appetite. On a behavioral level, this disease manifests as irritability, obsessions, compulsions, hallucinations, impaired memory, dementia and decreased ability to execute functions. Due to the location of the brain affected, these cognitive abnormalities are accompanied by motor abnormalities and impairment leading to (depending on the stage of the disease) disability in movement and coordination. Patients with early-stage Huntington disease have recently been shown to have reduced levels of branched chain amino acids (BCAA) which indicate an energy deficit with consequences reaching beyond the CNS. This energy deficit aspect which is seen in HD patients forms the basis of animal models used for the evaluation of potential drugs for HD.
Histone Deacetylyases (HDAC)
HDACs are enzymes that affect the acetylation status of histones and other important cellular proteins. The role of protein acetylation is an important post-translational modification that regulates cellular functions, including chromatin remodelling, transcriptional regulation, microtubular dynamics, intracellular transport, metabolism, and ageing. Levels of acetylation are controlled by histone acetylases (HATs) and HDACs which add or remove (respectively) acetyl groups from substrates. An increased acetylation (HAT activity) loosens the chromatin configuration leading to an increase in gene expression, while deacetylation (HDAC activity) condenses the chromatin leading to decreased gene expression and thus translation. Thus up-regulation of transcription can be achieved by the stimulation of HAT or the inhibition of HDAC.
HDAC Inhibitors and Polyglutamine-Repeat Disorders
HD is a polyglutamine-repeat disease and HDAC inhibitors have the potential to play an important therapeutic role in such diseases. The mechanism of neurodenegeration in certain polyglutamine-repeat diseases like HD are relatively well understood and is largely attributed to specific aspects of an aberration in neuronal homeostasis. This aberration is attributed to abnormal histone acetylation leading to a different chromatin remodelling thus leading to aberrant protein expression and interaction. Additionally the neuroprotective effect of HDAC inhibitors has been well documented in both invertebrate and mouse models for HD and other polyglutamine-repeat diseases.
Another aspect leading to the progression of HD is a defect in the microtubule-based transport which contributes to neuronal toxicity. In view of this, HDAC inhibition can compensate for the transport deficit by increasing α-tubulin acetylation. The HDAC responsible for the deacetylation of α-tubulin is the Class III HDAC called Sirtuins.
Sirtuins
Class III deacetylases or Sirtuins are named after “silent information regulator 2 (Sir2)” gene and are structurally different from other HDACs. There are 7 different kinds of sirtuins which have been identified and characterised and the main deacetylation activity is attributed to SIRT1, SIRT2, SIRT3 and SIRT5.
SIRT2 is a cystolic protein that deacetylates α-tubulin and microtubules and in specific is associated with the CNS since it has been shown to be localized to myelin sheaths and is implicated in the regulation of axonal myelination.
SIRT2 is responsible for the deacetylation of α-tubulin and the progression of HD is affected by the acetylated state of α-tubulin, an inhibition of SIRT2 can prove to be therapeutically effective in the treatment of HD.
An additional feature of HDAC inhibitors is that they are effective over a spectrum of diseases, mainly Polyglutamine-Repeat Diseases. Also HDAC inhibitors have improved selectivity, decreased toxicity, and have emerged as important drug targets.
Pterostilbene
Pterostilbene is a stilbenoid and is found in wine, peanuts, grapes, berries and certain species of Pterocarpous. Pterostilbene is one of the many aromatic hydrocarbons called ‘stilbenes’. This compound has potent anti-diabetic properties, chemoprotective properties and is also being investigated for its anti-cancer properties.
Animal Models for the Evaluation of Hd: 3-NP Model
A variety of methods are available to evaluate and/or monitor Huntington's disease. A variety of clinical symptoms and indicia for the disease are known. Based on the symptoms exhibited in HD, several animal models exist to evaluate potential drug candidates for this disease.
3-NP (Nitropropionic Acid) is known to cause symptoms of HD in rats. 3-NP is an inhibitor of mitochondrial respiration which on oxidation forms a covalent adduct with a catalytic-base arginine. Administration of 3-nitropropionic acid, an inhibitor of the mitochondrial citric acid cycle, produces a very selective striatal degeneration and results in a progressive locomotor deterioration in rodents resembling that of Huntington's disease.
US Pat. Pub. No.: S 2009/0069444 A1
This patent application refers to a composition which is used to treat oxidative stress and thereby renders an improvement in working memory of a subject when administered between dosage ranges of 2.5-20 mg/kg of body weight.
To establish the effect of the composition of the improvement of learning and memory this application uses the Morris Water Maze example. This is a method to test the spatial learning a memory of a subject and this test is dependant on the age and diet of the subject. This example concluded the effects of the diet containing Pterostilbene on cognitive performance and working memory. Further this example claims the use of Pterostilbene in the treatment of oxidative stress thereby improving cognitive function.
However there is no mention or indication of the use of Pterostilbene for the improvement of factors related to specific disorders of the CNS. It is important to note that although disorders of the CNS are age related, they cannot merely be attributed to oxidative stress. There can be a multitude of other factors mainly genetic and enzymatic ones which are involved and thus lead to the onset or progression of CNS diseases.
US Pat. Pub. No.: US 2007/0249647 A1
This patent application deals with the use of substituted cis or trans stilbenes for the treatment of cancer, pre-cancer conditions, inflammatory conditions and ischemic injuries like stroke. The primary method of action of the claimed composition of this patent application is by the inhibition of NF-κB activity. Based on this inhibition this application claims the use of the composition in diseases like diabetes and Alzheimer's.